淋巴细胞性脉络膜脑膜炎
细胞毒性T细胞
生物
CD8型
免疫学
慢性感染
白细胞介素21
封锁
免疫系统
T细胞
病毒学
受体
体外
生物化学
作者
Daniel L. Barber,E. John Wherry,David Masopust,Baogong Zhu,James P. Allison,Arlene H. Sharpe,Gordon J. Freeman,Rafi Ahmed
出处
期刊:Nature
[Springer Nature]
日期:2005-12-28
卷期号:439 (7077): 682-687
被引量:3461
摘要
Functional impairment of antigen-specific T cells is a defining characteristic of many chronic infections, but the underlying mechanisms of T-cell dysfunction are not well understood. To address this question, we analysed genes expressed in functionally impaired virus-specific CD8 T cells present in mice chronically infected with lymphocytic choriomeningitis virus (LCMV), and compared these with the gene profile of functional memory CD8 T cells. Here we report that PD-1 (programmed death 1; also known as Pdcd1) was selectively upregulated by the exhausted T cells, and that in vivo administration of antibodies that blocked the interaction of this inhibitory receptor with its ligand, PD-L1 (also known as B7-H1), enhanced T-cell responses. Notably, we found that even in persistently infected mice that were lacking CD4 T-cell help, blockade of the PD-1/PD-L1 inhibitory pathway had a beneficial effect on the 'helpless' CD8 T cells, restoring their ability to undergo proliferation, secrete cytokines, kill infected cells and decrease viral load. Blockade of the CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) inhibitory pathway had no effect on either T-cell function or viral control. These studies identify a specific mechanism of T-cell exhaustion and define a potentially effective immunological strategy for the treatment of chronic viral infections.
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